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Karsten Müssig, Harald Staiger, Fausto Machicao, Alena Stančáková, Johanna Kuusisto, Markku Laakso, Claus Thamer, Jürgen Machann, Fritz Schick, Claus D. Claussen, Norbert Stefan, Andreas Fritsche, Hans-Ulrich Häring, Association of Common Genetic Variation in the FOXO1 Gene with β-Cell Dysfunction, Impaired Glucose Tolerance, and Type 2 Diabetes, The Journal of Clinical Endocrinology & Metabolism, Volume 94, Issue 4, 1 April 2009, Pages 1353–1360, https://doi.org/10.1210/jc.2008-1048
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Abstract
Context: The transcription factor forkhead box protein (FOX) O1A plays a crucial role in regulation of β-cell function and metabolic effects of insulin in the liver.
Objective: The objective of the study was to investigate whether common genetic variation within the FOXO1 gene encoding FOXO1A contributes to prediabetic phenotypes, such as insulin resistance or β-cell dysfunction, and to risk of type 2 diabetes.
Design and Settings: Study I was a study enrolling thoroughly phenotyped subjects from Germany at increased risk for type 2 diabetes. Study II was a population-based study of Finnish men for the assessment of the prevalence of type 2 diabetes and metabolic syndrome.
Participants: Study I included 941 nondiabetic subjects (353 males, 588 females, aged 39 ± 1 yr, body mass index 29.2 ± 0.3 kg/m2). Study II included 5957 middle-aged men (870 type 2 diabetic and 5087 nondiabetic subjects).
Interventions: Genotyping for 10 single-nucleotide polymorphisms (SNPs) covering 100% of common genetic variation (minor allele frequency ≥10%) within the FOXO1 gene (r2 ≥ 0.8) based on HapMap data, oral glucose tolerance test, and in a subset additionally a hyperinsulinemic-euglycemic clamp.
Main Outcome Measurements: Parameters of insulin secretion, insulin resistance, and glucose tolerance status were measured.
Results: In the German subjects at increased risk for type 2 diabetes, SNPs rs2721068 and rs17446614 were significantly (P = 0.0045 and P = 0.0018, respectively) and SNPs rs17446593 and rs2297627 were nominally (P = 0.0091 and P = 0.0387, respectively) associated with β-cell dysfunction. rs2721068, rs17446614, and rs2297627 were also nominally associated with impaired glucose tolerance (P = 0.0264, P = 0.0162, and P = 0.0221, respectively). Minor allele carriers showed reduced insulin secretion and elevated glucose levels during an oral glucose tolerance test. Investigating the relevance of our findings in a separate cohort, we found that SNP rs2721068 was significantly associated with type 2 diabetes in the additive (P = 0.002) and dominant model (P = 0.009) in Finnish men.
Conclusions: Common genetic variation within the FOXO1 gene affects insulin secretion and glucose tolerance and associates with an increased risk of type 2 diabetes.
